uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A molecular atlas of cell types and zonation in the brain vasculature
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Blickagangen 6, SE-14157 Huddinge, Sweden..
Tianjin Med Univ, Key Lab Postneuroinjury Neurorepair & Regenerat C, Dept Neurosurg,Gen Hosp, Tianjin Neurol Inst,Minist Educ & Tianjin City, Tianjin 300052, Peoples R China..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.ORCID iD: 0000-0003-0700-4381
Show others and affiliations
2018 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 554, no 7693, p. 475-480Article in journal (Refereed) Published
Abstract [en]

Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2018. Vol. 554, no 7693, p. 475-480
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-349342DOI: 10.1038/nature25739ISI: 000425597400036PubMedID: 29443965OAI: oai:DiVA.org:uu-349342DiVA, id: diva2:1201789
Funder
AstraZenecaSwedish Research Council, 2015-00550, K2014-64X-20097-09-5EU, European Research Council, AdG294556Swedish Cancer Society, 150735, CAN 2016/271Knut and Alice Wallenberg Foundation, 2015.0030The Swedish Brain FoundationAvailable from: 2018-04-26 Created: 2018-04-26 Last updated: 2019-03-24Bibliographically approved
In thesis
1. The role of PDGF-B in brain blood vessels
Open this publication in new window or tab >>The role of PDGF-B in brain blood vessels
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The development of blood vessels is dependent on several molecular cues to form properly. A functional PDGF-B/PDGFR-b signaling is paramount for the investment of mural cells, that provide with support, to the developing vasculature. Mutations in PDGFB and PDGFRB are linked to PFBC, an age-dependent neurodegenerative condition manifested by vessel associated calcifications in the brain. The overall aim of the work presented in here was to investigate PFBC related calcifications and analyze the effects of impaired PDGF-B/PDGFR-b signaling on the formation of brain calcifications in different mouse models.

In paper I, we functionally analyzed PFBC-related PDGFB and PDGFRB mutations in vitro. While all PDGFB mutations lead to abolished protein function, PDGFRB mutations have more diverse consequences. We also show that reduced Pdgfb and Pdgfrb levels are insufficient for the formation of brain calcifications in several mouse strains. Moreover, region-specific susceptibility factors seem to reside in PFBC pathogenesis that are distinct from pericyte coverage and BBB deficiency.

In paper II, we described the molecular composition and cellular association of calcified nodules that develop in two mouse models of PFBC, Pdgfbret/ret and Slc20a2-/- mice. We show that the nodules are composed of pro- and anti-mineralization proteins and that they are in direct association with astrocytes and microglia

In paper III, we analyzed the effects of EC-specific ablation of PDGF-B in adult brain vasculature.  We report a substantial decrease of pericyte coverage and altered VSMC morphology and that this phenotype is inadequate to trigger the formation of calcifications or affect BBB integrity.

The aim of paper IV was to molecularly define the adult mouse brain vasculature by taking advantage of the scRNAseq technique. Here, we describe a gradual change in expression profile along the arteriovenous axis: ECs present a continuum along the axis while mural cell expression profile is punctuated. 

In summary, this thesis present detailed description of calcifications formed in mouse models of PFBC and address the role of impaired PDGF-B/PDGFR-b signaling for the formation of nodules in mice. Furthermore, the scRNaseq analysis performed on healthy adult brain vasculature has paved the way for future analysis in mouse models of PFBC.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 48
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1556
Keywords
PFBC, PDGFB, PDGFRB, Brain vasculature, Mural cells
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-380088 (URN)978-91-513-0607-0 (ISBN)
Public defence
2019-05-15, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2019-04-18 Created: 2019-03-24 Last updated: 2019-06-18

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Vanlandewijck, MichaelMäe, Maarja AndaloussiAndrae, JohannaAndo, KojiNahar, KhayrunLaviña, BàrbaraGouveia, Maria Leonor SeguardoBetsholtz, Christer

Search in DiVA

By author/editor
Vanlandewijck, MichaelMäe, Maarja AndaloussiAndrae, JohannaAndo, KojiNahar, KhayrunLaviña, BàrbaraGouveia, Maria Leonor SeguardoBetsholtz, Christer
By organisation
Vascular BiologyDepartment of Immunology, Genetics and Pathology
In the same journal
Nature
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 211 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf